Adoptive immunotherapy with transient anti-CD4 treatment enhances anti-tumor response by increasing IL-18Rα(hi) CD8(+) T cells

Adoptive T cell therapy (ACT) requires lymphodepletion preconditioning to eliminate immune-suppressive elements and enable efficient engraftment of adoptively transferred tumor-reactive T cells. As anti-CD4 monoclonal antibody depletes CD4(+) immune-suppressive cells, the combination of anti-CD4 treatment and ACT has synergistic potential in cancer therapy. Here, we demonstrate a post-ACT conditioning regimen that involves transient anti-CD4 treatment (CD4(post)). Using murine melanoma, the combined effect of cyclophosphamide preconditioning (CTX(pre)), CD4(post), and ex vivo primed tumor-reactive CD8(+) T-cell infusion is presented. CTX(pre)/CD4(post) increases tumor suppression and host survival by accelerating the proliferation and differentiation of ex vivo primed CD8(+) T cells and endogenous CD8(+) T cells. Endogenous CD8(+) T cells enhance effector profile and tumor-reactivity, indicating skewing of the TCR repertoire. Notably, enrichment of polyfunctional IL-18Rα(hi) CD8(+) T cell subset is the key event in CTX(pre)/CD4(post)-induced tumor suppression. Mechanistically, the anti-tumor effect of IL-18Rα(hi) subset is mediated by IL-18 signaling and TCR–MHC I interaction. This study highlights the clinical relevance of CD4(post) in ACT and provides insights regarding the immunological nature of anti-CD4 treatment, which enhances anti-tumor response of CD8(+) T cells.